Disappointing Early Results With PTK/ZK in Patients With Advanced Colorectal Cancer

ORLANDO-Preliminary data
from a randomized, double-blind, placebo-
controlled phase III trial showed
that the angiogenesis inhibitor PTK/
ZK added little to the efficacy of FOLFOX4
in first-line treatment of advanced
colorectal cancer. J. Randolph
Hecht, MD, of the University of California,
Los Angeles, presented the
study, which is known as the CONFIRM-
1 trial (abstract LBA3).

Dr. Hecht said that PTK/ZK is an
attractive candidate in this setting because
it is an oral, small-molecule vascular
endothelial growth factor
(VEGF) receptor inhibitor. Preliminary
studies showed that PTK/ZK produced
a rapid reduction in the amount
of contrast in colorectal tumors and
seemed to correlate with clinical benefit.
The multinational CONFIRM-1
study randomized 1,168 patients to
receive FOLFOX4 (oxaliplatin [Eloxatin]/
fluorouracil/leucovorin) with
either oral PTK/ZK (1,250 mg once
daily) or placebo. The study was sponsored
by Novartis and Schering.

Study Endpoints

The main study endpoints were disease
progression-free survival (PFS)
and overall survival. Dr. Hecht presented
data for PFS but not for OS.
The PFS hypothesis was that treatment
would produce a 25% reduction
in risk of disease progression (hazard
ratio [HR], 0.75). The OS hypothesis
was that 1-year survival would increase
by 71% to 76% (HR, 0.8). Dr. Hecht
reported data on 585 patients treated
with FOLFOX4 plus PTK/ZK and 583
patients treated with FOLFOX4 plus
placebo.

PTK/ZK produced a 12% reduction
in risk of progression in patients
with metastatic colorectal cancer when
given with initial FOLFOX4 chemotherapy,
but this difference did not
achieve statistical significance. A
planned secondary analysis showed a
reduction in risk of progression of
17%, which was statistically significant.

Grade 3/4 toxicities occurred in
more than 5% of patients and were
consistent with those associated with
FOLFOX4 alone. Most side effects
were mild to moderate, reversible, and
similar to those of other VEGF path-
way inhibitors (see Table 1).

Dr. Hecht stressed the importance
of testing other PTK/ZK dosing schedules
before drawing conclusions about
the drug's potential. Discussant Lee
Ellis, MD, agreed. Dr. Ellis (University
of Texas M.D. Anderson Cancer Center,
Houston), said, "Just because a
trial does not meet its primary endpoint
does not mean that the drug is
not active. He pointed out that recently
published work by Thomas et al
suggests that twice-daily dosing of
PTK/ZK is required to obtain optimal
efficacy due to the drug's pharmacokinetic
profile (Thomas AL, Morgan B,
Horsfield MA, et al: Phase I study of
the safety, tolerability, pharmacokinetics,
and pharmacodynamics of
PTK787/ZK 222584 administered
twice daily in patients with advanced
cancer. [Early Release, published online
ahead of print May 2, 2005, J Clin
Oncol.])